Project Summary: This proposal describes a five-year career development and training plan for Dr. Jason Homsy, who is an Instructor in Medicine at Brigham and Women?s Hospital (BWH), Boston. Dr. Homsy has outlined a career development plan and research proposal that leverages his training in genetics and extensive resources in the Harvard community with skills in computational biology, statistics, genome analysis and genome editing to shed novel insight into the genetic causes of congenital heart disease (CHD). Dr. Homsy is mentored by Christine E. Seidman, M.D., Thomas W. Smith Professor of Medicine and Genetics at Harvard Medical School and BWH who is both a distinguished clinical cardiologist and member of the Howard Hughes Medical Institute and National Academy of Sciences. Dr. C. Seidman works closely together with Dr. Jonathan Seidman, and both are world-renown human and molecular geneticists with a focus on cardiovascular genetics. Over the last twenty years, the Seidmans have mentored countless young investigators who go on to successful, independent research careers as physician scientists. Dr. Homsy?s career development plan includes educational resources at Harvard Medical School, BWH and the Broad Institute. Dr. Homsy has gathered an advisory committee that includes world experts in human genetics. This award will allow Dr. Homsy to continue studies on the genetic causes of CHD. He has shown that a significant number of children with CHD have spontaneous mutations (de novo mutations) that are damaging to protein function. Children with these mutations have a high likelihood of exhibiting additional disorders, such as neurodevelopmental and/or other birth defects, whereas a genetic cause of disease in children with isolated CHD is less clear. Additionally, the cause of disease in up to 80% of cases is still unknown. Dr. Homsy proposes that there is a class of CHD-causing variants in noncoding DNA (regulatory promoters and enhancers) that have not yet been identified. Supporting his hypothesis, many mutations in CHD that have been discovered are in genes such as transcription factors and chromatin modifiers that alter genome-wide transcriptional programs by interacting with noncoding DNA elements. Thus, mutations in these elements may be additional causes of CHD, particularly isolated CHD in which affected elements may be spatially and temporally restricted to heart development. Dr. Homsy?s research goals are to 1. Identify de novo mutations in noncoding DNA by whole genome sequencing of children with CHD but no identifiable genetic defect 2. Compare mutation rates in regulatory elements critical to heart development among CHD probands and control subjects with respect to an expectation model 3. Model mutations in iPS cells using CRISPR to determine effects on nearby gene expression 4. Functionally characterize noncoding elements according to clinical phenotypes of cases with mutations. Dr. Homsy will use this career development plan to build the foundation for becoming an independent academic physician scientist.